Long-Term Outcomes Associated With Permanent Pacemaker Implantation in Low-Risk Surgical Aortic Valve Replacement

Background Permanent pacemaker implantation is associated with an increased risk of mortality and heart failure after surgical aortic valve replacement (SAVR). Objectives The purpose of this study was to analyze long-term prognosis of permanent pacemaker implantation following SAVR on low-risk patients. Methods This nationwide, population-based, observational cohort study included all patients who underwent SAVR in Sweden between 2001 and 2018 with low surgical risk, defined as logistic EuroSCORE I <10% or EuroSCORE II <4%. Patients received a permanent pacemaker implantation within 30 days after SAVR. Main outcomes were all-cause mortality, heart failure hospitalization, and endocarditis. Regression standardization addressed confounding. Results We included 19,576 patients with low surgical risk. Of these, 732 (3.7%) patients received a permanent pacemaker within 30 days after SAVR. The mean age was 68 years and 33% were women. We found no difference in all-cause mortality between patients who received a pacemaker compared to those who did not (absolute survival difference at 17 years: 0.1% (95% CI: −3.6% to 3.8%). After 17 years, the estimated cumulative incidence of heart failure in patients who received a pacemaker was 28% (95% CI: 24%–33%) vs 20% (95% CI: 19%–22%) in patients who did not (absolute difference 8.2% [95% CI: 3.8%–13%]). We found no difference in endocarditis between the groups. Conclusions We found an increased incidence of heart failure in patients with low surgical risk who received a permanent pacemaker after SAVR. Permanent pacemaker implantation was not associated with all-cause mortality or endocarditis. Efforts should be made to avoid the need for permanent pacemaker following SAVR.

P ermanent pacemaker implantation is a known complication after both surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR).2][3] A previous study by our group showed that postoperative permanent pacemaker implantation after SAVR was associated with long-term mortality and increased rates of heart failure. 1 The long-term effects of permanent pacemaker implantation after TAVR may not be as severe. 4This might be explained by an older patient population with a higher surgical risk undergoing TAVR than SAVR, where other factors such as comorbidity and age may have a more important impact on survival and other long-term clinical outcomes.However, the effect of permanent pacemaker implantation after SAVR in patients with low surgical risk is not known.
Permanent pacemaker implantation in patients with low surgical risk may have a greater influence on long-term prognosis due to the low burden of comorbidities, compared to patients with a higher surgical risk.The impact of permanent pacemaker implantation in patients with low surgical risk is of increasing importance, both in terms of clinical decisions for the individual patient but also owing to the growing number of patients with low surgical risk subject to TAVR procedures. 1,4,5We therefore performed a follow-up study of our previous study 1 to investigate the prognosis after permanent pacemaker implantation following SAVR in the subset of patients who had low surgical risk.

MATERIAL AND METHODS
STUDY DESIGN.This was an observational, nationwide, population-based cohort study.This study was approved by the Swedish Ethical Review Authority and the requirement for informed consent was waived (registration number: 2020-04967).Study  OUTCOMES.The primary outcome was all-cause mortality, obtained from the Swedish Total Population Register. 9Secondary outcomes were the cumulative incidence of heart failure hospitalization and endocarditis, obtained from the National Patient Register. 10The corresponding International Classification of Diseases (ICD)-9 and ICD-10 codes were used to ascertain the secondary outcomes and exposure was obtained from the National Patient Register.The ICD codes used are presented in Supplemental Table 1.
DATA SOURCES.The Swedish Cardiac Surgery register, which is a part of the SWEDEHEART (Swedish Lu et al The standardized cumulative survival and differences in survival were estimated using flexible parametric regression standardization to account for baseline differences between the groups.The resulting survival curve estimates the population outcome if the entire population either received or did not receive a permanent pacemaker implantation.This method adjusts for the population distribution of covariates. 16,17Flexible hazard-based regression standardization was used to estimate the cumulative incidence and differences in heart failure hospitalization and endocarditis, as described by Kipourou et al. 18 The produced curves estimate the cumulative incidence of heart failure hospitalization and endocarditis if the entire population either received or did not receive a permanent pacemaker implantation. This method adjusts for the population distribution of covariates while accounting for the competing risk of death.Model selections for all-cause mortality, heart failure hospitalization, and endocarditis were performed using clinical subject matter knowledge and a backward selection strategy aided by the Akaike information criterion.The CART (Classification And Regression Tree) estimation and imputation approach 19 was used to handle missing data.Data were assumed to be missing at random.
We repeated the main analyses using inverse probability of treatment weighting (IPTW).Propensity scores were generated using generalized boosted regression modeling and stabilized weights were calculated for IPTW to account for differences in baseline characteristics between the pacemaker and non-pacemaker groups. 20The main analyses were also ENDOCARDITIS.During a mean follow-up of 6.6 years (maximum 18.0 years), 814 patients (4.2%) had endocarditis.After 17 years of follow-up, the regression standardized cumulative incidence for endocarditis was 7.9% (95% CI: 5.5%-11%) in the pacemaker group compared to 7.3% (95% CI: 6.6%-8.2%) in the no pacemaker group with a 0.6% (95% CI: -2.2% to 3.3%) difference between the groups (Table 2).The regression standardized cumulative incidence of endocarditis for both groups is shown in Figure 3.

DISCUSSION
In patients with low surgical risk, permanent pacemaker implantation after SAVR was associated with a higher risk of heart failure hospitalization compared to no permanent pacemaker implantation.There was  [95% CI: 1.04-1.17]). 24While the mechanism is not fully understood, it is likely that the dyssynchronous activation pattern in right ventricle pacing leads to adverse remodeling and decreased pumping ability of the ventricles. 25 a previous study from our group, the prognosis after permanent pacemaker implantation following SAVR was analyzed among 24,983 patients, who underwent SAVR in Sweden from 1997 to 2018 irrespective of surgical risk. 1 In this study, 3.4% of patients received a permanent pacemaker and the absolute risk difference for heart failure between patients with permanent pacemaker implantation and no pacemaker was 9.6% (95% CI: 4.9%-14.2%)after 15 years of follow-up.These results are similar to our study, where we found an absolute risk difference between pacemaker and no pacemaker of 7.5% (95% CI: 3.4%-12%) after 15 years.In contrast, the prior study also found a significant association between permanent pacemaker and all-cause mortality with an absolute risk difference of 4.9% at 15 years (95% CI: 0.5%-9.2%),while the current study showed a nonsignificant absolute risk difference of 0.1% (95% CI: -3.6% to 3.7%).It is possible that permanent pacemaker requires a certain burden of comorbidity to translate into increased mortality.Among patients with low surgical risk, this burden of comorbidity might not be sufficient to increase the mortality rate in patients with permanent pacemaker. Smilar to the prior study, we found no association between permanent pacemaker implantation after SAVR and endocarditis.

Lu et al
Although the current study constitutes a subgroup of patients from our prior publication that included patients irrespective of surgical risk, 1 we believe this study provides results and data that are novel, unique, and important.The solely inclusion of The ideal timing of permanent pacemaker implantation after surgery remains controversial.Some studies have found that only 40% to 45% of patients who had received permanent pacemaker implantation were dependent on pacemaker in the longterm. 28,29This suggests that some perioperative injuries of the heart conduction system may recover over time. 29While there is a clear indication for early permanent pacemaker implantation in patients with complete AV block with low or no escape rhythm following SAVR, 30 other perioperative injuries may be transient and resolve spontaneously. 28,29Consequently, the optimal timing of permanent pacemaker  ACKNOWLEDGMENTS The authors thank the SWE-DEHEART steering committee for providing data for this study.

FUNDING SUPPORT AND AUTHOR DISCLOSURES
reporting followed the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) and RECORD (REporting of studies Conducted using Observational Routinely collected health Data) guidelines.

13 A
Web-system for Enhancement and Development ofEvidence-based care in Heart disease Evaluated According to Recommended Therapies) registry, was used to identify the study population.11The Swedish Cardiac Surgery register records all patients who have undergone cardiac surgery in Sweden since 1992, and contains preoperative, perioperative, and postoperative data, including survival status through linkage with the Total Population Register.The Swedish Cardiac Surgery register has high reliability and validity.12The Swedish National Patient Register was used to obtain additional baseline characteristics, and outcome data for the hospitalization for heart failure and endocarditis outcomes.The heart failure diagnose has high reliability and high validity in the National Patient Register during external review.10,

SENSITIVITY ANALYSES.
Figures 2 to 4) and the analyses utilizing IPTW (Supplemental Figures 5 to 7) were consistent with the main analyses.

J
A C C : A D V A N C E S , V O L . 3 , N O .8 , 2 0 2 4 Pacemaker After Low-Risk Surgical Aortic Valve Replacement A U G U S T 2 0 2 4 : 1 0 1 1 1 0 no association between permanent pacemaker implantation and all-cause mortality, or endocarditis.Right ventricular pacing has been associated with an increased risk of heart failure.A study that included all 27,704 patients without prior heart failure who received a right ventricle lead in Denmark between 2002 and 2014 investigated the risk of heart failure compared to an age-and sex-matched control population. 24They found a higher risk for heart failure in patients with a right ventricle lead (HR: 1.11 CENTRAL ILLUSTRATION Long-Term Outcomes Associated With Permanent Pacemaker Implantation in Low-Risk Surgical Aortic Valve Replacement Lu R, et al.JACC Adv.2024;3(8):101110.Permanent pacemaker implantation after surgical aortic valve replacement in patients with low surgical risk was associated with an increased risk of heart failure in a nationwide cohort study including 19,576 patients operated between 2001 and 2018 in Sweden.J A C C : A D V A N C E S , V O L . 3 , N O .8 Pacemaker After Low-Risk Surgical Aortic Valve Replacement

FIGURE 1
FIGURE 1 Regression Standardized Survival and Difference in Survival implantation in patients with less severe conduction disturbances may warrant further research.While a delay in permanent pacemaker implantation might reduce unnecessary use, other factors such as risks associated with prolonged hospital stay and health economics must be taken into consideration.Our study is clinically relevant, especially in an era where more young patients with low surgical risk become subject to TAVR procedures.Younger patients with low surgical risk have a longer life expectancy,31 making adverse outcomes associated with permanent pacemaker implantation very relevant for this population in terms of quality-adjusted life years.

FIGURE 3 9 CONCLUSIONS
FIGURE 3 Regression Standardized Endocarditis and Difference in Endocarditis

4.
Rück A, Saleh N, Glaser N. Outcomes following permanent pacemaker implantation after transcatheter aortic valve replacement.JACC Cardiovasc Interv.2021;14:2173-2181. 5. Durko AP, Osnabrugge RL, Van Mieghem NM, et al.Annual number of candidates for transcatheter aortic valve implantation per country: current estimates and future projections.Eur Heart J. 2018;39:2635-2642.6. Benchimol EI, Smeeth L, Guttmann A, et al.The REporting of studies conducted using observational Routinely-collected health data (RECORD) statement.PLoS Med.2015;12:e1001885.7. von Elm E, Altman DG, Egger M, et al.The Strengthening the reporting of observational PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Clinicians are urged to exercise thorough consideration prior to making decisions regarding permanent pacemaker implantation in low surgical risk patients.Efforts should be taken to minimize the necessity for permanent pacemaker implantation after SAVR.TRANSLATIONAL OUTLOOK: Patients with low surgical risk who received a permanent pacemaker after SAVR had a higher risk of heart failure.Future investigations should prioritize examining the optimal timing for permanent pacemaker implantation after SAVR, a matter that remains controversial.Given the observed association of pacemaker implantation with adverse outcomes, a careful consideration of strategies aimed at their avoidance is needed.Lu et al J A C C : A D V A N C E S , V O L . 3 , N O .8 , 2 0 2 4 Pacemaker After Low-Risk Surgical Aortic Valve Replacement A U G U S T 2 0 2 4 : 1 0 1 1 1 0 8or patients operated between 2012 and 2018.8 6,7STUDY POPULATION AND EXPOSURE.The study included all patients with low surgical risk who underwent primary SAVR in Sweden between January 1, 2001, and December 31, 2018.Low surgical risk was defined as a logistic EuroSCORE I <10%, for patients operated between 2001 and 2011, or EuroSCORE II <4%, classify the exposure, baseline, and outcome procedures.The study population constitutes a subgroup of our previous study, 1 including only patients with low surgical risk.All patients in this study were included in our previous study.

TABLE 1
Baseline Characteristics of Patients With and Without Permanent Pacemaker Implantation After Surgical Aortic Valve Replacement Between 2001 and 2018 in Sweden [21][22][23]a subset of patients who underwent isolated SAVR.All statistical analyses and data management were performed using the R programming language, version 4.2.0 (R Foundation for Statistical Computing) and included the use of the "survival," "mexhaz," and "rstpm2" packages.[21][22][23]MISSINGDATA.Missing data were present in the following variables: left ventricular ejection fraction (9.6%), body mass index (7.3%),preoperativedialysis(5.4%),estimatedglomerularfiltrationrate(2.9%),education level (0.9%), and valve size (0.8%).left ventricular ejection fraction <30% (4.5% in the pacemaker group vs 1.8% in the no pacemaker group).Baseline characteristics are presented in Table1.The rate of permanent pacemaker implantations per year increased during the study period, as shown in Supplemental Figure1.The distribution of pacemaker implantations within 30 days following SAVR is shown in Supplemental Figure11.HEART FAILURE HOSPITALIZATION.During a mean follow-up of 6.5 years (maximum 18.0 years), 2,113 patients (10.8%) were hospitalized for heart failure.After 17 years of follow-up, the regression standardized cumulative incidence for heart failure hospitalization was 28% (95% CI: 24%-33%) in the pacemaker group compared to 20% (95% CI: 19%-22%) in the no pacemaker group, with an 8.2% (95% CI: 3.8%-13%) difference between the groups (Table2; Central Illustration).The regression standardized cumulative incidence of heart failure hospitalization for both groups is shown in Figure2.

TABLE 2
Regression Standardized Cumulative Incidence and Differences for All-Cause Mortality, Heart Failure Hospitalization, and Endocarditis Among Patients With Low Surgical Risk Who Underwent Surgical Aortic Valve Replacement in Sweden Values are % (95% CI).Adjusted by regression standardization.Model covariates included were postoperative permanent pacemaker implantation, age, sex, hospital, left ventricular ejection fraction, concomitant coronary artery bypass, ascending aortic surgery, birth region, education level, prior atrial fibrillation, history of cancer, diabetes mellitus, prior endocarditis, prior heart failure, hyperlipidemia, hypertension, hepatic disease, prior peripheral vascular disease, prior stroke, prior major bleeding event, prior percutaneous coronary intervention, household income, categorical body mass index, period of surgery, categorical estimated glomerular filtration rate, categorical valve size, isolated AVR, and bioprothesis.A detailed description and precise model specification for the different outcomes is available in the Supplemental Appendix.
Schörling Foundation, and Mr Fredrik Lundberg.The authors have reported that they have no relationships relevant to the contents of this paper to disclose.implantation and surgical aortic valve replacement.Interact Cardiovasc Thorac Surg.2013;17:328-333.3. Popma JJ, Deeb GM, Yakubov SJ, et al.Transcatheter aortic-valve replacement with a Self-Expanding valve in low-risk patients.N Engl J Med. 2019;380:1706-1715.